Association of dengue severity with the serotype of infection: a systematic review and meta-analysis

Background Dengue is a mosquito-borne infection caused by one of four dengue virus serotypes (DENV1-4) that circulates endemically across the tropics and subtropics. To date, there is contrasting evidence on the relationship between the serotype of infection and disease severity. Methods We conducted a systematic review (PROSPERO, CRD42023443101) and meta-analysis to examine the association between the serotype of symptomatic infections with severe disease while accounting for both prior exposure status and geographic region, with 18 severity defined by (i) the 1997 World Health Organization (WHO) guidelines, (ii) the 2009 WHO guidelines or (iii) hospitalisation. We searched the Global Health, Embase Classic + Embase, and Medline databases using Ovid for studies published up to 20 January 2025 and extracted case counts with matched serotype and severity information. We fitted generalised linear mixed models to estimate the proportions of severe cases, running independent analyses per severity definition, and stratifying by prior exposure-serotype combinations (e.g. primary DENV2) and geographic region (Asia versus Americas). Heterogeneity was assessed using the 𝜏 26 and 𝐼 metrics and risk of bias was assessed by adapting an established tool for risk of bias in prevalence studies. 28 Findings Our search yielded 4621 unique records, with 71 studies included for the meta-analysis. We found that, on average, DENV3 in Asia resulted in the highest proportion of DHF/DSS (21·00% [95% CrI: 13·02 to 30·44%]) and hospitalised (22·00% [95% CrI: 0·88 to 75·31%]) cases among symptomatic primary infections, while also causing the highest proportion